This is a Multiple-PI R01 proposal for coordinated investigation of the striatum, a brain structure critically involved in normal movement and motivation. Altered striatal function underlies a range of serious, common neurological disorders, including Parkinson's Disease and dystonia. Yet the mechanisms by which this structure normally processes information, and how this can go awry, are not well understood. One particular cell type, the fast-spiking interneuron (FSI), is rare but has a disproportionate influence over other striatal neurons. Loss of FSIs has been observed in animal models of dystonia and in human Tourette syndrome. In recent studies we have observed activation of FSIs as highly trained yet unwanted choices need to be suppressed, and that selective suppression of FSIs results in dystonia-like symptoms. FSIs thus appear to have a key coordinating role within striatal networks, and there is a pressing need to better understand their physiological and behavioral functions. The proposed complementary experiments in brain slices and awake behaving animals make full use of advanced electrophysiological, pharmacological and optogenetic methods. Aim 1 examines how distinct inputs from cortex, thalamus, and globus pallidus influence FSI firing patterns, both spontaneously and at critical moments of choice task performance. Aim 2 examines the conditions under which FSIs control striatal projection cells of the two major output pathways, and how FSI suppression affects network dynamics and behavior. Finally, Aim 3 investigates the consequences of dopamine loss on striatal microcircuits, examining changes in local connectivity and firing patterns that may underlie core movement difficulties in Parkinson's Disease. The long-term goals of this research program are to determine the fundamental operational principles of striatal circuits from sub-cellular to network levels. This knowledge would be of immense value in designing improved therapies for Parkinson's Disease, dystonia, Tourette Syndrome and other serious brain disorders. PUBLIC HEALTH RELEVANCE: This proposal aims to reveal how microcircuitry within a specific brain structure contributes to normal behavioral control, and how dysfunction of this structure results in abnormal behavior. Greater understanding of this circuitry would be of immense value in designing improved therapies for Parkinson's Disease, dystonias, Tourette Syndrome and other serious brain disorders.